Pain is the most common symptom for which patients seek medical advice and treatment. While acute pain is usually self-limited, chronic pain can persist for 3 months or longer and lead to significant changes in a patient's personality, lifestyle, functional ability and overall quality of life (K. M. Foley, Pain, in Cecil Textbook of Medicine 100-107, J. C. Bennett and F. Plum eds., 20th ed. 1996).
Pain has traditionally been managed by administering either a non-opioid analgesic (such as acetylsalicylic acid, choline magnesium trisalicylate, acetaminophen, ibuprofen, fenoprofen, diflunisal or naproxen), or an opioid analgesic (such as morphine, hydromorphone, methadone, levorphanol, fentanyl, oxycodone or oxymorphone).
Although the term “narcotic” is often used to refer to opioids, the term is not specifically applicable to opioids. The term “narcotic”, derived from the Greek word for “stupor”, originally referred to any drug that induced sleep, only later being associated with opioids (Gutstein, Howard B., Akil, Huda, “Chapter 21. Opioid Analgesics” (Chapter 21), Brunton, L L, Lazo, J S, Parker, K I: Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11th Edition: http://www.accessmedicine.com/content.aspx?aID=940653). In the legal context, the term “narcotic” refers to a variety of mechanistically unrelated substances with abuse or addictive potential (Gutstein, Howard B., Akil, Huda, “Chapter 21. Opioid Analgesics” (Chapter 21), Brunton L L, Lazo J S, Parker K I: Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11th Edition: http://www.accessmedicine.com/content.aspx?aID=940653). Thus, the term “narcotic” not only refers to opioids, but also refers to such drugs as cocaine, methamphetamine, ecstasy, etc., which exert their pharmacological effects via different receptors than opioids. Furthermore, because the term “narcotic” refers to such a wide variety of unrelated drugs, many of which do not possess analgesic properties, it cannot be assumed that a drug that has “narcotic” properties is necessarily analgesic. For example, drugs such as ecstasy and methamphetamine are not analgesic, and are not used to treat pain.
Until recently, there was evidence of three major classes of opioid receptors in the central nervous system (CNS), with each class having subtype receptors. These receptor classes are known as μ, δ and κ. As opiates have a high affinity to these receptors while not being endogenous to the body, research followed in order to identify and isolate the endogenous ligands to these receptors. These ligands were identified as endorphins, enkephalins, and dynorphins, respectively. Additional experimentation has led to the identification of the opioid receptor-like (ORL-1) receptor, which has a high degree of homology to the known opioid receptor classes. This newly discovered receptor was classified as an opioid receptor based only on structural grounds, as the receptor did not exhibit pharmacological homology. It was initially demonstrated that non-selective ligands having a high affinity for μ, δ and κ receptors had low affinity for the ORL-1 receptor. This characteristic, along with the fact that an endogenous ligand had not yet been discovered, led to the ORL-1 receptor being designated as an “orphan receptor”.
Subsequent research led to the isolation and structure of the endogenous ligand of the ORL-1 receptor. This ligand, nociceptin (also known as orphanin FQ (OFQ)), is a seventeen amino acid peptide structurally similar to members of the opioid peptide family. (C. Altier et al., “ORL-1 receptor-mediated internalization of N-type calcium channels.” Nature Neuroscience, 2005, 9:31).
The discovery of the ORL-1 receptor and its endogenous ligand, presents an opportunity for the discovery of novel compounds that can be administered for pain management or other syndromes influenced by this receptor.
Many publications in the ORL-1/nociceptin field provide evidence that activation of ORL-1 receptors in the brain can inhibit opioid-mediated analgesia (e.g., D. Barlocco et al., “The opioid-receptor-like 1 (ORL-1) as a potential target for new analgesics.” Eur. J. Med. Chem., 2000, 35:275; J. S. Mogil et al., “Orphanin FQ is a functional anti-opioid peptide.” Neurosci., 1996, 75:333; K. Lutfy et al., “Tolerance develops to the inhibitory effect of orphanin FQ on morphine-induced antinociception in the rat.” NeuroReport, 1999, 10:103; M. M. Morgan et al., “Antinociception mediated by the periaqueductal gray is attenuated by orphanin FQ.” NeuroReport, 1997, 8:3431; and J. Tian et al., “Involvement of endogenous Orphanin FQ in electroacupuncture-induced analgesia.” NeuroReport, 1997, 8:497).
A growing body of evidence supports a more generalized regulatory role for ORL-1 against the actions of the μ receptor, possibly contributing to the development of μ-agonist tolerance in patients being treated with classical opiates (e.g., J. Tian et al., “Functional studies using antibodies against orphanin FQ/nociceptin.” Peptides, 2000, 21:1047; and H. Ueda et al., “Enhanced Spinal Nociceptin Receptor Expression Develops Morphine Tolerance and Dependence.” J. Neurosci., 2000, 20:7640). Moreover, ORL-1 activation appears to have an inhibitory effect on the rewarding properties of several drugs of abuse, including μ agonists.
Certain compounds have been described as at least partial agonists for ORL-1 (e.g., buprenorphine (IC50 of 8.4 nM), fentanyl (IC50 of about 10,000 nM), 7-benzylidenenaltrexone (IC50 about 10,000 nM) (S. Wnendt et al., “Agonistic effect of buprenorphine in a nociceptin/OFQ receptor-triggered reporter gene assay.” Molec. Pharmacol., 1999, 56:334-338), and etorphine (IC50 of about 2000 nM) (Hawkinson et al., “Opioid activity profiles indicate similarities between the nociceptin/orphanin FQ and opioid receptors.” Eur. J. Pharmacol, 2000, 389:107-114)). However, buprenorphine's μ potency is disclosed to be much greater than its ORL-1 potency.
Recent data have shown that the analgesic efficacy of buprenorphine is enhanced by pre-treatment with an ORL-1 receptor antagonist. Using the tail-flick test in mice, Lutfy et al. demonstrated that buprenorphine's typical bell-shaped dose-response curve (wherein low and high doses induce little analgesia, and mid-range doses produce maximal analgesia) is eliminated by pre-treatment with the ORL-1 antagonist J-113397, and analgesic efficacy is improved at the higher range of doses (K. Lutfy et al., “Buprenorphine-induced antinociception is mediated by μ-opioid receptors and compromised by concomitant activation of opioid receptor-like receptors.” J. Neurosci., 2003, 23:10331-10337).
Recently, a multidisciplinary group of experts in the fields of pharmacology, toxicology, pain management, and anesthesia have recommended buprenorphine as the best opioid for treating chronic severe pain in elderly patients (Pergolizzi, et al. (2008). Opioids and the Management of Chronic Severe Pain in the Elderly: Consensus Statement of an International Expert Panel with Focus on the Six Clinically Most Often Used World Health Organization step IB Opioids (buprenorphine, Fentanyl, Hydromorphone, Methadone, Morphine, Oxycodone. Pain Practice 8(4): 287-313). It was found that of the opioids studied, buprenorphine provided the best analgesic-to-side effect profile. Buprenorphine was the most effective opioid for treating neuropathic pain. Buprenorphine was the only opioid for which metabolism was not affected by impaired renal function. Buprenorphine was the only opioid demonstrating a ceiling effect for respiratory depression, indicating that higher doses may be used. Also, buprenorphine was the least likely to induce immunosuppression. The panel of experts attributed the improved therapeutic efficacy of buprenorphine to its unique pharmacological profile.
Buprenorphine has also been shown to have an improved side effect profile in animal models. A review of recent data in animal models of reward and addiction has shown that buprenorphine has a low addictive and dependence-inducing profile compared to other opioids (Tzschentike (2002). Behavioral pharmacology of buprenorphine, with a focus on preclinical models of reward and addiction. Psychopharmacology 161: 1-16).
Use of opioid analgesics often leads to constipation as a side effect. Constipation associated with the use of opioid analgesics is presumed to occur primarily and mechanistically as a result of the action of μ opioid agonists directly upon μopioid receptors located in the bowel (Wood & Galligan (2004), Function of opioids in the enteric nervous system. Neurogastroenterology & Motility 16(Suppl. 2): 17-28). Stimulation of the μ opioid receptors in the bowel causes inhibition of normal gastrointestinal (GI) motility, leading to constipation. The effect of μ opioid agonism on μ opioid receptors in the bowel can be observed via the action of loperamide (Imodium™) in treating diarrhea. Loperamide is a potent μ opioid agonist that is administered orally, but which has little to no absorption into the blood stream. As a result, loperamide exerts its action locally upon the μ opioid receptors in the bowel, and this results in inhibition of GI motility, which treats diarrhea.
There has been recent interest in developing combinations of μ receptor agonists and antagonists having defined biodistribution properties that might serve to limit opioid-induced constipation. For example, the co-administration of an orally bio-available μ opioid receptor agonist (such as morphine, codeine, oxycodone or hydrormorphone) together with a potent μ opioid receptor antagonist (such as N-methylnaloxone or N-methylnaltrexone) that is not orally bio-available may serve to prevent or reduce the constipation otherwise associated with μ opioid receptor agonist therapy. The rationale is that the agonist component will be absorbed and distributed throughout the periphery and the central nervous system (CNS), resulting in the desired analgesia, while the antagonist component will remain in the bowel where it will prevent or reduce any agonist-induced constipation that might otherwise occur.